PROJECT SUMMARY/ABSTRACT The prevalence of Alzheimer's disease (AD) and related dementias is increasing at alarming rates given the rapidly burgeoning older adult population. Since no interventions to impact disease progression currently exist, there has been significant interest in identifying the very earliest risk factors and prevention targets. Central to this effort is research aimed at characterizing the neurobiological changes that underlie mild cognitive impairment (MCI), a period thought to represent the transition between normal aging and dementia. Indeed, studies have shown that cerebral white matter (WM) degradations may represent one of the earliest detectable brain changes in individuals at-risk for dementia (Brickman et al., 2015), and considerable evidence suggests that both elevated vascular (e.g., hypertension, arterial stiffness) and genetic risk (i.e., apolipoprotein E [APOE] genotype) serve central roles in either driving or contributing to observed WM changes across the aging spectrum (Saji, Toba, & Sakurai, 2016; Nation et al., 2015; Wang et al., 2015). Although WM structural changes in aging and MCI have been well characterized in the cerebrum, the presence of such changes has yet to be explored in the brainstem. This represents a critical gap in the literature, especially since data have demonstrated the considerable vulnerability of the brainstem to vascular insult. Indeed, approximately 25% of all strokes and transient ischemic attacks occur in the vertebrobasilar distribution (Flossmann & Rothwell, 2003). Moreover, there has been a recent resurgence in interest in the brainstem given Braak and del Tredici's (2015) work showing that AD pathology may initiate within and propagate from this region. However, few studies exist given a historical lack of sensitive imaging technology capable of differentiating between the small, densely-packed brainstem structures, and none have evaluated brainstem WM integrity as it relates to novel vascular risk factors (i.e., arterial stiffness) and APOE-e?4 status in the context of MCI. Thus, this multi-modal study proposes to leverage sensitive imaging techniques (multi-shell diffusion tensor imaging [DTI]) optimized for the brainstem region, combined with sensitive diagnostic and vascular risk assessment, to comprehensively investigate brainstem WM integrity in a sample of well-characterized older adults with and without MCI. Specific aims include: (1) determining whether participants with MCI demonstrate reduced brainstem WM integrity compared to cognitively intact older adults; and (2) characterizing the contribution of increased vascular and genetic risk to brainstem WM integrity in older adults with and without MCI. Exploratory analyses will investigate the differences in the relationship between vascular and genetic risk and brainstem WM across MCI subtypes using our novel MCI diagnostic scheme (Jak et al., 2009) that has demonstrated increased sensitivity to early cognitive impairment, biomarkers of AD (e.g., CSF amyloid and tau), and cognitive decline (Bondi et al., 2015; Edmonds et al., 2015, 2016). Importantly, findings of this proposal could serve to elucidate the role of brainstem WM alterations in MCI, while also informing targeted vascular- and genetic-based prevention and intervention strategies that may reduce the development and progression of dementias such as AD.